A trial to learn how effective and safe datopotamab deruxtecan (Dato-DXd) is compared to docetaxel and how well Dato-DXd works in adults with advanced or metastatic TROP2-positive, non-squamous non-small cell lung cancer (NS-NSCLC).

Prior treatment

• History of another primary malignancy other than NSCLC, except for malignancy treated with curative intent with no known active disease within 3 years before randomisation and of low potential risk for recurrence.
• Spinal cord compression or brain metastases, unless asymptomatic, stable, and not requiring treatment with corticosteroids or anticonvulsants for at least 7 days prior to randomisation.

Other illness

• NSCLC disease that is eligible for definitive local therapy alone.
• Clinically significant corneal disease.
• Has active or uncontrolled hepatitis B or C virus infection.
• Known HIV infection that is not well controlled.
• Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
• History of non-infectious ILD/pneumonitis including radiation pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.

Other

• Squamous, mixed NSCLC, or SCLC histology.
• Has severe pulmonary function compromise per Investigator discretion.

• Pathologically documented Stage IIIB, IIIC, or Stage IV non-squamous NSCLC without AGA at the time of randomisation and meets the criteria for NSCLC: * Participants must have documented negative test results for EGFR, ALK, and ROS1 genomic alterations. * Has no known tumour genomic alterations in NTRK, BRAF, RET, MET exon 14 skipping, KRAS G12C, HER2 or any other actionable driver oncogenes for which there are locally approved and available targeted first-line therapies. * Prospectively assessed TROP2 QCS-NMR positive based on results from an appropriately validated investigational TROP2 RxDx device.
• Documentation of radiographic disease progression while on or after receiving the most recent treatment regimen for advanced or metastatic NSCLC.
• Participants must have received platinum-based chemotherapy (PBC) in combination with anti-PD-1/anti-PD-L1 mAb as the only prior line of therapy or received PBC and anti-PD-1/anti-PD-L1 monoclonal antibody (in either order) sequentially as the only 2 prior lines of therapy.
• Provision of acceptable FFPE tumour sample for assessment of TROP2.
• At least one lesion not previously irradiated that qualifies as a RECIST 1.1 TL at baseline and can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes, which must have short axis ≥ 15mm) with CT or MRI and is suitable for accurate repeated measurements.
• ECOG PS of 0 or 1.
• Adequate bone marrow reserve and organ function within 7 days before randomisation.